Agent for preventing, improving or treating hypertension

ABSTRACT

The invention relates to an agent for preventing, improving or treating hypertension, which exhibits a hypotensive effect, inhibits the rise of blood pressure and improves hypertension, and food for preventing or improving hypertension, which does not become a burden in daily intake, has a higher antihypertensive effect and is useful as a diet during treatment for patients of hypertension. The agent for preventing, improving or treating hypertension contains the following components (A) and (B):
         (A) a compound selected from the group consisting of caffeic acid, chlorogenic acid and ferulic acid, and esters and pharmaceutically acceptable salts thereof; and   (B) a component selected from the group consisting of central nervous system stimulating components, food fibers, extracts of perennial evergreen leaves of the genus  Camellia, Theaceae , or  Eucommia ulmoides  Oliver,  Eucommiae , organic acids having a molecular weight of 60 to 300 (excluding citric acid) and pharmaceutically acceptable salts thereof, and sugar alcohols.

This application is a divisional of U.S. patent application Ser. No.09/944,079 filed Sep. 4, 2001, now U.S. Pat. No. 6,991,812.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an agent for preventing, improving ortreating hypertension, which permits inhibiting the rise of bloodpressure and moreover improving hypertension and is useful as food anddrink, and food such as food for specific health in addition to a drugfor preventing, improving or treating hypertension.

2. Description of the Background Art

Cardiac diseases such as angina pectoris, myocardial infarction andheart failure, and cerebrovascular diseases such as cerebral infarction,cerebral hemorrhage and subarachnoid hemorrhage very closely relate tohypertension and stand second and third, respectively, in the Japanesecauses of death. According to the basis research (the 1998 year) of thenational life by the Ministry of Health and Welfare, the number ofpatients going to hospital regularly with hypertension is sixty-four perthousand in Japan and stands first in the cause of decease. As acountermeasure against the hypertension, may be mentioned the use ofantihypertensive drugs such as diuretics, sympatholytic depressants,vasodilators and angiotensin converting enzyme inhibitors. These drugsare mainly applied to serious patients of hypertension. On the otherhand, general treatments aiming at improving life custom, such asdietetic therapy, therapeutic exercise and restriction of smoking anddrinking, are widely applied to slight and serious patients ofhypertension. Therefore, the importance of general treatments isrecognized. Among others, improvement in the custom of eating is said tobe important, and there are many foods traditionally said to have ahypotensive effect. Antihypertensive materials derived from food haveheretofore been extensively searched, and isolation and identificationof active ingredients having a hypotensive effect have been made inlarge numbers. Juices of immature fruits of apple, sand pear, peach andthe like, which belong to Rosaceae, contain fruit polyphenol having aninhibitory effect on an angiotensin I converting enzyme (ACE), andcaffeic acid and chlorogenic acid have an ACE-inhibiting effect. It hasbeen proposed to use such a fruit juice as an antihypertensive agent(Japanese Patent Application Laid-Open No. 259453/1996).

However, under the circumstances, many of drugs used for the purpose oftreating hypertension are satisfactory in effectiveness, whereaspatients are heavily burdened with their side effects, such astachycardia and bradycardia, existing in no small numbers. With respectto foods said to have a hypotensive effect, or active ingredientsthereof, the effectiveness is not always satisfactory. Further, many ofthem require a long time to develop a hypotensive effect.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an agent forpreventing, improving or treating hypertension, which is excellent insafety, does not become a burden in daily intake and has a higherantihypertensive effect.

The present inventors have found that the combined use of a compoundsuch as caffeic acid, chlorogenic acid or ferulic acid with a specificplant, plant extract or organic acid permits markedly inhibiting therise of blood pressure compared with the single use of these compounds,and is suitable for use in drugs and food.

According to the present invention, there is thus provided an agent forpreventing, improving or treating hypertension, comprising the followingcomponents (A) and (B):

(A) a compound selected from the group consisting of caffeic acid,chlorogenic acid and ferulic acid, and esters and pharmaceuticallyacceptable salts thereof; and

(B) a component selected from the group consisting of central nervoussystem stimulating components, food fibers, extracts of perennialevergreen leaves of the genus Camellia, Theaceae, or Eucommia ulmoidesOliver, Eucommiae, organic acids having a molecular weight of 60 to 300and pharmaceutically acceptable salts thereof, and sugar alcohols.

According to the present invention, there is also provided a foodcomprising such an agent for preventing, improving or treatinghypertension.

According to the present invention, there is further provided use of theabove-described components (A) and (B) for preparation of an agent forpreventing, improving or treating hypertension.

According to the present invention, there is still further provided amethod of treating hypertension, which comprises administering effectiveamounts of the components (A) and (B).

The agent for preventing, improving or treating hypertension accordingto the present invention exhibits a hypotensive effect, inhibits therise of blood pressure, improves hypertension and is useful as an agentfor preventing, improving or treating hypertension. Besides, the agentdoes not become a burden in daily intake, has a higher antihypertensiveeffect and is useful as a diet during treatment for patients ofhypertension and also as food and drink for preventing or improvinghypertension, food such as food for specific health, and a quasi-drug.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The component (A) used in the present invention may be a productchemically synthesized. However, an extract of a natural substancecontaining this component, particularly, a plant may be used. Examplesof the plant include coffee, onion, radish, lemon, MOROHEIYA, Cnidiumofficinale Makino, Angelica acutiloba Kitagawa, pine, Captis japonicaMakino, asafetida, sugarcane, corn, barley and rice.

Caffeic acid and chlorogenic acid may also be extracted from a plantsuch as green beans of coffee, leaves of nandin or an immature fruit ofapple. For example, an acid obtained by extraction of seeds of Coffeaarabica LINNE, Rubiaceae with hot water or with an aqueous solution ofascorbic acid or citric acid under heating may be used.

Ferulic acid is a compound contained, as an ester thereof, in naturalsubstances, particularly plants such as rice and adlay and may beobtained as a purified product from such a plant or a synthesizedproduct industrially obtained. A ferulic ester is obtained in a hydrousethanol fraction after rice bran oil obtained from rice bran ispartitioned with hydrous ethanol and hexane at room temperature underweakly alkaline conditions. Ferulic acid can be obtained by hydrolyzingthe ferulic ester obtained by the above-described process with sulfuricacid with heating under pressure and purifying the resultant hydrolyzateor by culturing Pseudomonas in a medium containing clove oil from budsand leaves of Syzygium aromaticum MERRILL et PERRY, Myrtaceae by steamdistillation, or eugenol obtained by purifying the clove oil andsubjecting the medium to isolation and purification. When ferulic acidis prepared by chemical synthesis, it may be prepared by, for example, acondensation reaction of vanillin and malonic acid (Journal of AmericanChemical Society, 74, 5346, 1952).

Incidentally, stereoisomers exist in caffeic acid, chlorogenic acid,ferulic acid or pharmaceutically acceptable salts thereof. However, purestereoisomers or a mixture thereof may be used in the present invention.The term “chlorogenic acid” in the present specification meanschlorogenic acid or a derivative thereof and designates 3-caffeoylquinicacid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3,4-dicaffeoylquinicacid,3,5-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid,3-feruloylquinic acid, 4-feruloylquinic acid, 5-feruloylquinic acid,3-feruloyl-4-caffeoylquinic acid or a mixture thereof.

Esters of caffeic acid, chlorogenic acid and ferulic acid include thosenaturally contained in natural substances, particularly, plants, thoseobtained by conversion by a chemical treatment upon extraction and/orfractionation and those chemically modified. Specific examples thereofinclude esters with an alcohol having 1 to 40 carbon atoms, i.e., estercompounds with a linear or branched alkyl or alkenyl alcohol, allylalcohol, terpene alcohol, sterol or trimethylsterol, and esters withplant sterol. As with ferulic acid, their corresponding esters ofcaffeic acid and chlorogenic acid may be used.

The solubility of caffeic acid, chlorogenic acid and ferulic acid inwater can be improved by providing them in the form of apharmaceutically acceptable salt, and their physiological effectivenesscan be enhanced. Examples of a basic substance used for forming such asalt include inorganic bases such as alkali metal or alkaline earthmetal hydroxides, for example, such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, magnesium hydroxide and calciumhydroxide; and ammonium hydroxide; and organic bases, such as basicamino acids such as arginine, lysine, histidine and ornithine; andmonoethanolamine, diethanolamine and triethanolamine with the alkalimetal or alkaline earth metal hydroxides being particularly preferred.The agents according to the present invention may be formulated eitherby preparing such a salt and adding the salt to other components, or byseparately adding a salt-forming component and a component to be formedinto a salt to other components to react them in the formulation system.

Two or more of the above-described compounds may be used in combinationas the component (A) according to the present invention.

In the agent according to the present invention for preventing,improving or treating hypertension, the component (A) may be containedin a proportion of 0.001 to 5% by weight (hereinafter indicated merelyby “%”), preferably 0.005 to 5%, more preferably 0.005 to 1%,particularly preferably 0.01 to 1%.

As the component (B) used in the present invention, the central nervoussystem stimulating components serve to stimulate the central nervoussystem to induce an exciting effect and are preferably selected from thegroup consisting of heat components of ginger, red pepper, pepper andthe like. Ginger, red pepper and pepper are known as spice.

As ginger, red pepper and pepper, plants belonging to Zingiberaceae,Capsicum and Piperaceae, respectively, are used. With respect to theheat components of these plants, cinerol, zingerone, zingerol, shogaoland the like are contained in a proportion of 0.6 to 10% in ginger,capsaicin and the like are contained in a proportion of about 20% in redpepper, and piperine or the like are contained in a proportion of about6 to 13% in pepper. These heat components may be either extractsobtained by solvent extraction making use of an organic solvent or thelike, or commercially available products. Two or more of these heatcomponents may be used in combination.

When the component (B) is a central nervous system stimulatingcomponent, it is preferably contained in a proportion of 0.001 to 1%,particularly 0.005 to 0.5% in the agent according to the presentinvention for preventing, improving or treating hypertension.

Specific examples of the food fibers as the component (B) used in thepresent invention include wheat bran composed of exodermis (testa andembryo) prepared by sieving in a milling process of wheat, beet fibersprepared by sieving after grinding of beet pulp, corn fibers prepared bypurifying an exodermis division obtained from a wet milling process ofcorn flour, apple fibers prepared by drying pulp (residue aftersqueezing of juice, and the like) derived from an apple fruit, celluloseprepared by hydrolyzing pulp and then purified and drying thehydrolyzate, hardly digestible dextrin prepared by partially hydrolyzingstarch, further hydrolyzing the partial hydrolyzate with amylase andthen decoloring and desalting the hydrolyzate, a decomposed product ofguar gum prepared by subjecting guar gum taken out of guar, which is aleguminous plant in an Indian region, to an enzymatic treatment, thyriumtesta prepared by grinding testa and exodermis of a plant ofPlataginaceae, alginic acid extracted from tang or low molecular sodiumalginate prepared by heating and hydrolyzing alginic acid to lower themolecular weight of alginic acid, thereby enhancing the solubilitythereof, chitin which is a basic polysaccharide purified by treating acrab shell or the like, or chitosan obtained by leaving the acetylgroups in chitin to make soluble in an acid solution, glucomannanpurified by grinding a tuberous root of devil's-tongue to remove starchand washing the resultant devil's-tongue flour with alcohol or water,and lignin which is a phenolic high molecular compound prepared as it isfrom pulp, hull or bran of cacao or other plants, or from a productobtained by subjecting it to a physiochemical treatment or chemicalpretreatment.

Carrageenan, agar, xanthan gum, durane gum, pullulan, pectin, methylcellulose, which are generally used in food, may also be mentioned.

As the food fibers, are particularly-preferred chitosan, lignin, hardlydigestible dextrin, alginic acid and low molecular sodium alginate. Twoor more of these food fibers may be used in combination.

When the component (B) is food fiber, a drink or food is preferablyprovided.

When the component (B) is food fiber, it is preferably contained in aproportion of 0.1 to 20%, particularly 0.5 to 10% in the agent accordingto the present invention for preventing, improving or treatinghypertension.

Examples of the extracts of perennial evergreen leaves of the genusCamellia, Theaceae as the component (B) used in the present inventioninclude parched (Chinese style) green tea and roasted (Japanese style)green tea as unfermented tea, HOSHU tea and oolong tea as semi-fermentedtea, and black tea (leaf, broken, etc.) as fermented tea.

Examples of the extract of Eucommia ulmoides Oliver include thoseproduced by subjecting leaves collected from Eucommia ulmoides Oliver,Eucommiae to solar drying and roasting.

These extracts are preferably extracts with water or an organic solvent.Examples of the organic solvent include methanol, ethanol, acetic acid,ethyl acetate, n-hexane, acetone, benzene, petroleum ether andchloroform. Extracts with ethanol or water are more preferred. Theextracts may be used as it is. However, concentrates obtained bypartially removing the solvent, or powders obtained by removing thesolvent may be used. Two or more of these extracts may be used incombination. The extracts of Eucommia ulmoides Oliver and oolong tea arepreferred.

A preferred combination with the component (A) includes a combination offerulic acid and the extract of oolong tea or Eucommia ulmoides Oliver,and a combination of ferulic acid and the extract of oolong tea is morepreferred from the viewpoint of easy drinking in view of continuous useor intake.

When the component (B) is one of these extracts, it is contained in aproportion of 0.1 to 10%, particularly 1 to 5% in terms of solids in theagent according to the present invention for preventing, improving ortreating hypertension.

Examples of the organic acids having a molecular weight of 60 to 300 asthe component (B) used in the present invention include carboxylicacids, hydroxycarboxylic acids, polycarboxylic acids, keto-carboxylicacids and the like from the viewpoint of structure, and specificexamples thereof include acetic acid, lactic acid, citric acid, gluconicacid, fumaric acid, α-ketoglutaric acid, succinic acid, glycolic acid,malic acid, tartaric acid, pyruvic acid and malonic acid. As the organicacids, are preferred other organic acid than citric acid.

Those naturally contained in natural substances, particularly, plants,those converted by a chemical treatment upon extraction and/orfractionation and those chemically modified are also included. Examplesof those derived from the natural substances include brewed vinegarprescribed in the Japanese Agricultural Standard and extracts thereof.The term “brewed vinegar” as used herein means vinegar made by aceticacid fermentation, and specific examples thereof include grain vinegarusing rice or other grains as a raw material, for example, grain vinegarcalled “black vinegar” made by stationary brewing by a single-stagefermentation making use of brown rice and koji as raw materials, fruitvinegar making use of apple, grape or any other fruit, and other brewedvinegar than grain vinegar and fruit vinegar. Fruit juices or extractsthereof may also be used. Specific examples thereof include juices offruits such as orange, mandarin orange, apple, grape, pineapple, peach,grapefruit, lemon, Japanese pear, pear, Japanese apricot, navel orange,strawberry, passion fruits, melon, lime, guava, apricot, SHIKUWASSHA,kabosu orange, shaddock, iyokan orange, hassaku orange, cranberry,banana, Japanese plum, mango, kiwi fruit, persimmon and ASERORA, mixedjuices and concentrates thereof, and extracts thereof with water,ethanol, methanol, acetic acid, chloroform, dichloromethane, ethylacetate, n-hexane, acetone, benzene, petroleum ether, ether or the like.Extracts with water or ethanol are particularly preferred.

Two or more of these organic acids may be used in combination.

When the component (B) is an organic acid having a molecular weight of60 to 300, it is contained in a proportion of 0.0005 to 10%,particularly 0.001 to 6% in the agent according to the present inventionfor preventing, improving or treating hypertension.

Examples of the sugar alcohols as the component (B) used in the presentinvention include those naturally contained in natural substances,particularly, plants, those converted by a chemical treatment uponextraction and/or fractionation and those chemically modified. Specificexamples of the sugar alcohols used include those obtained by reducingthe carbonyl groups in monosaccharides, oligosaccharides,polysaccharides and the like to convert them to their correspondingalcohols. Specific examples of monosaccharide alcohols includeerythritol which is a sugar alcohol of a tetrose, xylitol from apentose, and sorbitol and mannitol from a hexose, which are selected byfermentationally decomposing glucose with yeast. Specific examples ofoligosaccharide alcohols include parathinit (reduced parathinose),maltitol (reduced maltose) and lactitol of disaccharide sugars, andbranched oligosaccharide alcohols. Specific examples of polysaccharidealcohols include reduced dextrin used as reduced starch syrup.

Among these, erythritol, xylitol, maltitol, parathinit, reduced dextrinand branched oligosaccharide alcohols are preferred.

Two or more of these sugar alcohols may be used in combination.

When the component (B) is a sugar alcohol, it is contained in aproportion of 0.1 to 70%, particularly 1 to 50% in the agent accordingto the present invention for preventing, improving or treatinghypertension.

When the agent according to the present invention for preventing,improving or treating hypertension is used as a medicine, apharmaceutically acceptable carrier may be added to the above-describedactive components to prepare an oral or parenteral composition. Forms ofthe oral composition include tablets, granules, grains, pills, powder,capsules (including hard capsules and soft capsules), troches, chewablepreparations and solutions (drinks). On the other hand, forms of theparenteral composition include intravenously administering preparationssuch as injections, suppositories, and external skin care preparations.

When the agent according to the present invention for preventing,improving or treating hypertension is used as a food, other food stuffsmay be added to the active ingredients of the components (A) and (B).Examples of the food include drinks and foods, and foods for specifichealth, such as drinks such as juice and coffee; liquid foods such assoup; emulsion or paste foods such as milk or curry; semisolid foodssuch as jelly or gumi; solid foods such as gum, bean curd or supplement;powdered foods; and oil-containing foods such as margarine, mayonnaiseand dressing. Drinks are particularly preferred.

The effective dose of the agent according to the present invention forpreventing, improving or treating hypertension per day for an adult(body weight: 60 kg) is as follows:

When the component (B) is a central nervous system stimulatingcomponent, caffeic acid, chlorogenic acid, ferulic acid or apharmaceutically acceptable salt thereof is preferred as the component(A). The component (A) is preferably ingested in a dose of 0.001 to 10g, particularly 0.01 to 5 g, while the central nervous systemstimulating component is preferably ingested in a dose of 0.0001 to 1 g,particularly 0.001 to 0.5 g.

When the component (B) is food fiber, the component (A) is preferablyingested in a dose of 0.001 to 10 g, particularly 0.005 to 5 g, and thefood fiber is preferably ingested in a dose of 0.1 to 50 g, particularly1 to 10 g.

When the component (B) is an extract of perennial evergreen leaves ofthe genus Camellia, Theaceae, or Eucommia ulmoides Oliver, Eucommiae,the component (A) is preferably ingested in a dose of 0.001 to 10 g,particularly 0.005 to 5 g, and the extract is preferably ingested in adose of 0.01 to 50 g, particularly 0.05 to 10 g in terms of solids.

When the component (B) is an organic acid having a molecular weight of60 to 300 or a pharmaceutically acceptable salt thereof, the component(A) is preferably ingested in a dose of 0.0001 to 5 g, particularly0.0005 to 1 g in terms of ferulic acid, and the organic acid or the likeis preferably ingested in a dose of 0.0001 to 5 g, particularly 0.0005to 1 g in terms of citric acid.

When the component (B) is a sugar alcohol, the component (A) ispreferably ingested in a dose of 0.001 to 10 g, particularly 0.005 to 5g, and the sugar alcohol is preferably ingested in a dose of 0.1 to 50g, particularly 1 to 20 g.

EXAMPLES Testing Method of Inhibiting the Rise of Blood Pressure in Rat

(a) Animal Used:

The blood pressure of each of male spontaneous hypertensive rats (SHR)was preliminarily continuously measured for 7 days by means of acommercially available non-invasive sphygmomanometer (manufactured bySoftlon Co.), thereby fully accustoming the rats to thesphygmomanometry, and an evaluation test was then started. All the ratswere bred (in a breeding chamber in a rat zone) under conditions of atemperature of 25±1° C., a relative humidity of 55±10% and a lightingtime of 12 hours (from 7 a.m. to 7 p.m.).

(b) Testing Method:

Six or eight SHRs were used as a group. The systolic blood pressure of atail artery of each rat was measured after 4 weeks from the beginning ofthe test.

(c) Statistical Processing Method:

The thus-obtained test results were expressed by a mean and standarderror to conduct a Student's t-test. A level of significance was definedas at most 5%.

Example 1 Central Nervous System Stimulating Component

In Control Group, drinking water and a commercially available powderedfeed were freely ingested. In Comparative Group 1, a solution withferulic acid (product of Wako Pure Chemical Industries, Ltd.) added towater at a concentration of 0.2% was used as drinking water, and acommercially available powdered feed was freely ingested. In Test Group1, a solution with caffeic acid (product of Wako Pure ChemicalIndustries, Ltd.) added to water at a concentration of 0.2% was used asdrinking water, and a feed with capsaicin (product of Wako Pure ChemicalIndustries, Ltd.; 0.1%) incorporated into a commercially availablepowdered feed was freely ingested. In Test Group 2, a solution withchlorogenic acid (product of Wako Pure Chemical Industries, Ltd.) addedto water at a concentration of 0.2% was used as drinking water, and afeed with zingerol (product of Matsuura Yakugyo K.K.; 0.1%) incorporatedinto a commercially available powdered feed was freely ingested. In TestGroup 3, a solution with ferulic acid added to water at a concentrationof 0.2% was used as drinking water, and a feed with piperine (product ofWako Pure Chemical Industries, Ltd.; 0.1%) incorporated into acommercially available powdered feed was freely ingested. In each group,6 rats aged 7 weeks at the time the intake test was started were used.

The systolic blood pressures in each group before the administration andafter 4 weeks from the administration are shown in Table 1. As apparentfrom Table 1, a marked inhibitory effect on the rise of blood pressurewas observed by using caffeic acid, chlorogenic acid, ferulic acid orthe pharmaceutically acceptable salt thereof and the Central nervoussystem stimulating component in combination.

TABLE 1 Systolic blood pressures (mmHg) After 4 weeks from Beforeadministration administration Control Group 146.2 ± 4.2 201.0 ± 4.9Comp. Group 1 148.8 ± 3.8 190.7 ± 3.4 Test Group 1 146.8 ± 4.8 181.5 ±3.4* Test Group 2 144.1 ± 3.5 180.3 ± 3.6* Test Group 3 145.6 ± 4.5178.7 ± 4.1* *There is a significant difference at a significance levelof at most 5% as against Control Group and Comparative Group 1. Eachvalue is expressed by mean ± standard error.

Example 2 Central Nervous System Stimulating Component (ImmediateEffect)

Six rats aged 15 weeks at the time the administration test was startedwere used in each group. The systolic blood pressure of a tail artery ofeach rat was measured after 1 hour from the beginning of theadministration.

In Control Group, water was orally administered. In Comparative Group 1,a 0.2% aqueous solution of ferulic acid was orally administered. In TestGroup 1, an aqueous solution containing caffeic acid (0.2%) andcapsaicin (0.1%) was orally administered. In Test Group 2, an aqueoussolution containing chlorogenic acid (0.2%) and zingerol (0.1%) wasorally administered. In Test Group 3, an aqueous solution containingferulic acid (0.2%) and piperine (0.1%) was orally administered.

The systolic blood pressures in each group before the administration andafter 1 hour from the administration are shown in Table 2. As apparentfrom Table 2, marked lowering of blood pressure was observed.

TABLE 2 Systolic blood pressures (mmHg) After 1 hour from Beforeadministration administration Control Group 209.6 ± 4.3 206.2 ± 4.4Comp. Group 1 206.1 ± 2.6 196.4 ± 3.9 Test Group 1 208.5 ± 3.4 178.1 ±5.8* Test Group 2 207.1 ± 3.0 180.3 ± 5.2* Test Group 3 208.9 ± 4.5179.5 ± 4.6* *There is a significant difference at a significance levelof at most 5% as against Control Group and Comparative Group 1. Eachvalue is expressed by mean ± standard error.

Example 3 Food Fiber

In Control Group, drinking water and a commercially available powderedfeed were freely ingested. In Test Group 1, a feed with chitosan (5%)incorporated into a commercially available powdered feed was freelyingested. In Test Group 2, a solution with caffeic acid added to waterat a concentration of 0.2% was used as drinking water, and a feed withchitosan (5%) incorporated into a commercially available powdered feedwas freely ingested. In Test Group 3, a solution with chlorogenic acidadded to water at a concentration of 0.2% was used as drinking water,and a feed with chitosan (5%) incorporated into a commercially availablepowdered feed was freely ingested. In Test Group 4, a solution withferulic acid added to water at a concentration of 0.2% was used asdrinking water, and a feed with chitosan (5%) incorporated into acommercially available powdered feed was freely ingested. In Test Group5, a solution with sodium ferulate added to water at a concentration of0.2% was used as drinking water, and a feed with chitosan (5%)incorporated into a commercially available powdered feed was freelyingested. In Test Group 6, a solution with cycloartenol ferulate addedto water at a concentration of 0.2% was used as drinking water, and afeed with chitosan (5%) incorporated into a commercially availablepowdered feed was freely ingested. In each group, 6 rats aged 7 weeks atthe time the intake test was started were used.

The systolic blood pressures in each group before the administration andafter 4 weeks from the administration are shown in Table 3. As apparentfrom Table 3, marked lowering of blood pressure was observed by usingcaffeic acid, chlorogenic acid, ferulic acid, or the ester orpharmaceutically acceptable salt thereof and the food fiber incombination as compared with the single administration of the foodfiber.

TABLE 3 Systolic blood pressures (mmHg) After 4 weeks from Beforeadministration administration Control Group 152.1 ± 4.4 201.0 ± 3.9 TestGroup 1 153.4 ± 2.9 186.7 ± 4.5* Test Group 2 154.0 ± 4.3 173.5 ±4.3**^(#) Test Group 3 155.1 ± 3.9 170.6 ± 4.2**^(#) Test Group 4 153.7± 4.8 169.7 ± 5.0**^(#) Test Group 5 155.7 ± 3.2 172.9 ± 4.6**^(#) TestGroup 6 152.9 ± 3.0 168.1 ± 4.7**^(#) *,**There are significantdifferences at significance levels of at most 5% and 1% as againstControl Group, respectively. ^(#)There is a significant difference at asignificance level of at most 5% as against Test Group 1. Each value isexpressed by mean ± standard error.

Example 4 Extract of Perennial Evergreen Leaves of the Genus Camellia,Theaceae

In Control Group, drinking water and a commercially available powderedfeed were freely ingested. In Test Group 1, a solution with ferulic acid(product of Wako Pure Chemical Industries, Ltd.) dissolved in drinkingwater at a concentration of 0.2% was freely ingested. In Test Group 2,drinking water and a feed with powdered green tea extract (“RyokuchaShokubutsu MF”, trade name, product of Maruzen Seiyaku K. K.; 3%)incorporated into a commercially available powdered feed were freelyingested. In Test Group 3, a solution with ferulic acid added to waterat a concentration of 0.2% was used as drinking water, and a feed withthe powdered green tea extract (3%) incorporated into a commerciallyavailable powdered feed was freely ingested. In Test Group 4, a solutionwith chlorogenic acid (product of Wako Pure Chemical Industries, Ltd.)added to water at a concentration of 0.2% was used as drinking water,and a feed with powdered oolong tea extract (“Sunoolong”, trade name,product of Suntory Limited; 3%) incorporated into a commerciallyavailable powdered feed was freely ingested. In each group, 6 rats aged16 weeks at the time the intake test was started were used.

The systolic blood pressures in each group before the administration andafter 4 weeks from the administration are shown in Table 4. As apparentfrom Table 4, the compositions according to the present invention foreating and drinking were observed having a marked effect to lower bloodpressure.

TABLE 4 Systolic blood pressures (mmHg) After 4 weeks from Beforeadministration administration Control Group 146.2 ± 4.2 201.0 ± 4.9 TestGroup 1 144.1 ± 2.8 190.4 ± 3.3* Test Group 2 145.0 ± 4.4 191.8 ± 3.9*Test Group 3 144.7 ± 4.0 180.3 ± 2.2*^(#) Test Group 4 145.1 ± 5.3 179.2± 2.7*^(#) *There is a significant difference at a significance level ofat most 5% as against Control Group. ^(#)There is a significantdifference at a significance level of at most 5% as against Test Groups1 and 2. Each value is expressed by mean ± standard error.

Example 5 Extract of Eucommia ulmoides Oliver

Evaluation as to lowering of blood pressure was made in the same manneras in Example 4.

In Control Group, drinking water and a commercially available powderedfeed were freely ingested. In Test Group 1, drinking water and a feedwith powdered extract of tea leaves of Eucommia ulmoides Oliver(“Tochucha Ekisu”, trade name, product of Matsuura Seiyaku K. K.; 3%)incorporated into a commercially available powdered feed were freelyingested. In Test Group 2, a solution with ferulic acid added to waterat a concentration of 0.2% was used as drinking water, and a feed withthe powdered extract (3%) of tea leaves of Eucommia ulmoides Oliverincorporated into a commercially available powdered feed was freelyingested. In Test Group 3, drinking water and a feed with powderedtriterpenyl ferulate mixture (1%) derived from rice bran and thepowdered extract (3%) of tea leaves of Eucommia ulmoides Oliverincorporated into a commercially available powdered feed were freelyingested.

The systolic blood pressures in each group before the administration andafter 4 weeks from the administration are shown in Table 5. As apparentfrom Table 5, marked lowering of blood pressure was observed byingesting the compositions according to the present invention for eatingand drinking.

TABLE 5 Systolic blood pressures (mmHg) After 4 weeks from Beforeadministration administration Control Group 146.2 ± 4.2 201.0 ± 4.9 TestGroup 1 144.3 ± 3.8 188.6 ± 4.2* Test Group 2 146.0 ± 3.9 174.3 ±3.1*^(#) Test Group 3 145.1 ± 4.6 172.8 ± 4.0*^(#) *There is asignificant difference at a significance level of at most 5% as againstControl Group. ^(#)There is a significant difference at a significancelevel of at most 5% as against Test Group 1. Each value is expressed bymean ± standard error.

Example 6 Organic Acid (Immediate Effect)

Six rats aged 15 weeks at the time the administration test was startedwere used in each group. The systolic blood pressure of a tail artery ofeach rat was measured after 1 hour from the beginning of oraladministration.

In Control Group, drinking water was orally administered forcedly bymeans of a metal-made stomach tube. In Comparative Group 1, a 0.1%aqueous solution of malic acid was orally administered. In ComparativeGroup 2, a 0.1 aqueous solution of ferulic acid was orally administered.In Test Group 1, an aqueous solution containing malic acid (0.1%) andferulic acid (0.1%) was orally administered.

The systolic blood pressures in each group before the administration andafter 1 hour from the administration are shown in Table 6. As apparentfrom Table 6, marked lowering of blood pressure was observed byadministering the composition according to the present invention.

TABLE 6 Systolic blood pressures (mmHg) After 1 hour from Beforeadministration administration Control Group 206.8 ± 3.4 198.0 ± 5.6Comp. Group 1 206.1 ± 2.6 196.4 ± 3.9* Comp. Group 2 208.0 ± 4.1 179.7 ±4.4*^(#) Test Group 1 207.4 ± 3.3 170.6 ± 2.1***^(#) *,***There aresignificant differences at significance levels of at most 5% and 0.1% asagainst Control Group, respectively. ^(#)There is a significantdifference at a significance level of at most 5% as against ComparativeGroup 2. Each value is expressed by mean ± standard error.

Example 7 Sugar Alcohol

In Control Group, a 1% aqueous solution of sugar was used as drinkingwater, and a commercially available solid feed was freely ingested. InTest Group 1, an aqueous solution containing ferulic acid (product ofWako Pure Chemical Industries, Ltd.; 0.1%) and sugar (1%) was used asdrinking water, and a commercially available solid feed was freelyingested. In Test Group 2 (Invention), an aqueous solution containingferulic acid (0.1%) and erythritol (product of Wako Pure ChemicalIndustries, Ltd.; 1%) was used as drinking water, and a commerciallyavailable solid feed was freely ingested. In each group, 8 rats aged 8weeks at the time the intake test was started were used.

The systolic blood pressures in each group before the administration andafter 4 weeks from the administration are shown in Table 7. As apparentfrom Table 7, a marked inhibitory effect on the rise of blood pressurewas observed by ingesting the invention composition in Test Group 2.

TABLE 7 Systolic blood pressures (mmHg) After 4 weeks from Beforeadministration administration Control Group 148.1 ± 3.2 195.0 ± 4.3 TestGroup 1 148.3 ± 3.6 187.1 ± 3.2 Test Group 2 148.5 ± 4.1 180.7 ± 3.8**There is a significant difference at a significance level of at most 5%as against Control Group. Each value is expressed by mean ± standarderror.

Example 8 Sugar Alcohol (Immediate Effect)

Six rats aged 15 weeks at the time the administration test was startedwere used in each group. The systolic blood pressure of a tail artery ofeach rat was measured after 1 hour from the beginning of oraladministration.

In Control Group, a 1% aqueous solution of sugar was orallyadministered. In Test Group 1, an aqueous solution containing ferulicacid (0.2%) and sugar (1%) was orally administered. In Test Group 2, anaqueous solution containing ferulic acid (0.2%) and erythritol (1%) wasorally administered. The dose was determined to be 15 mL/kg.

The systolic blood pressures in each group before the administration andafter 1 hour from the administration are shown in Table 8. As apparentfrom Table 8, marked lowering of blood pressure was observed byadministering the composition according to the present invention.

TABLE 8 Systolic blood pressures (mmHg) After 1 hour from Beforeadministration administration Control Group 206.8 ± 3.4 207.2 ± 3.2 TestGroup 1 208.0 ± 3.5 184.6 ± 3.4** Test Group 2 208.3 ± 4.6 175.7 ±2.4**^(#) *,**There are significant differences at significance levelsof at most 5% and 1% as against Control Group, respectively. ^(#)Thereis a significant difference at a significance level of at most 5% asagainst Test Group 1. Each value is expressed by mean ± standard error.

Example 9 Soft Capsule Preparation

Composition of soft capsule: Gelatin 70.0% Glycerol 22.9 Methylp-hydroxybenzoate 0.15 Propyl p-hydroxybenzoate 0.51 Water 6.44 The softcapsule (oval form, weight: 150 mg)composed of the above composition was charged with the followingcomponents to prepare a soft capsule preparation.

TABLE 9 (mg) No. 1 2 3 Ferulic acid 50 50 50 capsaicin 100 Powderedgreen tea extract 450 Maltitol 450

All the soft capsule preparations Nos. 1 to 3 exhibited a good effect tolower blood pressure.

Example 10 Cookie

Cookies composed of their corresponding compositions shown in Table 10were baked.

TABLE 10 (g) No. 4 5 6 7 8 Ferulic acid 1 Cycloartenol ferulate¹⁾ 1 1 1Extract of coffee bean 1 Piperine 1 Lignin 15 Powdered extract of oolongtea 5 Orange extract 5 5 Reduced dextrin 14 Cacao extract 5 Rapeseed oil15 10 15 12 Soybean oil 15 Corn starch 15 15 15 12 Wheat 50 44 46 50 40Butter 5 5 5 5 5 Fructose 14 14 14 14 Common salt 0.5 0.5 0.5 0.5 Bakingsoda 0.5 0.5 0.5 0.5 Water 10 10 10 10 ¹⁾Product of Wako Pure ChemicalIndustries, Ltd.

These cookies Nos. 4 to 8 were tasty and observed permitting beingingested by adults suffering from hypertension.

Example 11 Healthy Drink

Healthy drinks composed of their corresponding compositions shown inTable 11 were prepared.

TABLE 11 (%) No. 9 10 11 12 13 14 Sodium ferulate 3.5 Ginger extract 0.10.1 0.1 0.1 0.1 Lactic acid 0.1 0.1 0.1 0.1 0.1 0.1 Malic acid 0.1Alginic acid 3.5 Powdered extract of tea 5.0 leaves of Eucommia ulmoidesOliver Lemon extract 3.5 3.5 3.5 Parathinit 9.0 Nonfat milk 3.5 3.5 3.53.5 3.5 3.5 Fructose 9.0 9.0 9.0 9.0 9.0 Ascorbic acid 0.1 0.1 0.1 0.10.1 0.1 Perfume base 0.1 0.1 0.1 0.1 0.1 0.1 water 83.6 83.6 82.1 83.683.6 83.6

All the healthy drinks Nos. 9 to 14 were high in shelf stability, goodin flavor and tasty.

Four adult men (the highest blood pressure: 135 mmHg) who were somewhathigh in blood pressure were got to drink the healthy drink No. 10 (200ml) every day for 4 weeks. As a result, lowering of the blood pressureby 7 mmHg was observed.

Example 12 Separate Type Dressing

Olive oil 40.0% Wine vinegar 50.0 Common salt  1.25 Pepper  0.3 Sodiumcaffeate  0.1 Granular mustard  8.35

A separate type dressing composed of the above composition was prepared.

1. A method for treating hypertension comprising: administering acomposition consisting essentially of: (A) an isolated compound selectedfrom the group consisting of caffeic acid or an ester or salt thereof,chlorogenic acid or an ester of salt thereof, and ferulic acid or anester or salt thereof; and (B) one or more isolated heat component(s) ofZingiberaceae or Capsicum; wherein said isolated heat component is atleast as hot as cinerol, zingerone, zingerol, shogaol, or capsaicin. 2.The method of claim 1, wherein (A) is isolated chlorogenic acid or anester or salt thereof.
 3. The method of claim 1, wherein (A) is ferulicacid or an ester or salt thereof.
 4. The method of claim 1, wherein (A)is caffeic acid or an ester or salt thereof.
 5. The method of claim 1,wherein component (B) is at least one isolated heat component of ginger.6. The method of claim 1, wherein component (B) comprises isolatedcinerol.
 7. The method of claim 1, wherein component (B) comprisesisolated zingerone.
 8. The method of claim 1, wherein component (B)comprises isolated zingerol.
 9. The method of claim 1, wherein component(B) comprises isolated shogaol.
 10. The method of claim 1, whereincomponent (B) is at least one isolated heat component of red pepper. 11.The method of claim 1, wherein component (B) comprises isolatedcapsaicin.
 12. The method of claim 1, wherein component (A) is isolatedchlorogenic acid or an ester of salt thereof, and component (B) isisolated zingerol or isolated capsaicin.
 13. The method of claim 1,wherein said composition contains 0.01-1 of (A) and 0.005-0.5% of (B).14. The method of claim 1, where components (A) and (B) are administeredas a composition which contains 0.01-1% of (A) which is chlorogenic acidor an ester or salt thereof, and 0.005-0.5% of (B) which is zingerol orcapsaicin.
 15. A method for treating hypertension comprising:administering a composition consisting essentially of: (A) isolatedchlorogenic acid or an ester of salt thereof; and (B) at least oneisolated heat component of Zingiberaceae, or Capsicum, wherein said heatcomponent is at least as hot as cinerol, zingerone, zingerol, shogaol,or capsaicin.